Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=2)[C:22]([C:37]#[N:38])=[C:21](SC2C=CC=CC=2)[N:20]=1.Cl>COCCOC.O>[NH2:18][C:19]1[N:20]=[C:21]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[C:22]([C:37]#[N:38])=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][OH:36])=[CH:31][CH:32]=2)[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cccc(CO)c1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(N)nc(OCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.65 g (14.68 mmol) of potassium tert-butoxide were suspended in 15 ml of 1,2-dimethoxyethane. After addition of 0.97 g (5.87 mmol) of 3-(hydroxymethyl)benzenecarboxylic acid (Example 66A) and 1.14 g (2.94 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 35A), the mixture was stirred at 60° C. overnight. After cooling of the reaction mixture, 50 ml of water were added. With ice-cooling, the clear solution was acidified to pH 1 using conc. hydrochloric acid. The aqueous phase was decanted from the viscous precipitate formed. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid). The aqueous phase was evaporated and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [CH:1]([Si:4]([CH:7]([CH3:9])[CH3:8])(Cl)[Cl:5])([CH3:3])[CH3:2].C([Si](C(C)C)(OC)[O:14][CH3:15])(C)C>>[CH:1]([Si:4]([CH:7]([CH3:9])[CH3:8])([O:14][CH3:15])[Cl:5])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Reactant: CO[Si](OC)(C(C)C)C(C)C
Product: CO[Si](Cl)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
A 500 ml-capacity, four-necked flask was charged with 18.5 g (0.1 moles) of diisopropyldichlorosilane and 17.6 g (0.1 moles) of diisopropyldimethoxysilane, and the resulting mixture was stirred at 20° C.-30° C. for 1 hour. There occurred a disproportionation reaction, thus giving a mixture comprising diisopropylmethoxychlorosilane, the unreacted diisopropyldichlorosilane and the unreacted diisopropyldimethoxysilane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[NH2:19])=[CH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:35][CH2:34][CH:30]([C:31]([Cl:33])=[O:32])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[ClH:33].[F:18][C:14]1[C:15]([F:17])=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:20])=[C:12]([NH:19][C:31]([CH:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=3)[CH2:35][CH2:34]2)=[O:32])[CH:13]=1
Reactant: COc1ccc(NC(=O)c2cc(F)c(F)cc2N)cc1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: COc1ccc(NC(=O)c2cc(F)c(F)cc2NC(=O)C2CCN(c3ccncc3)CC2)cc1
Product: Cl
Yield: 55.8 %

Procedure:
Using the procedure described in Example 138, N-(4-methoxyphenyl)-2-amino-4,5-difluorobenzamide (1.8 mmol) and N-(4-pyridyl)isonipecotoyl chloride (3.6 mmol), purifying with RPHPLC Method A, yielded 505 mg (57%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOC(C)=O>[CH3:28][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Yield: 97.3 %

Procedure:
In a 100 mL round bottomed flask equipped with magnetic stirring was added tert-butyl 4-{2-[(methylsulfonyl)-amino]phenyl}-piperazinecarboxylate (Preparation III) (692 mg, 1.947 mmol) and DMF (5 mL). After stirring 5 min, NaH (60% oil dispersion) (100 mg, 2.5 mmol) (Aldrich) in DMF (10 mL) was added. The reaction was stirred 20 min, then iodomethane (190 μl, 3.05 mmol) (Aldrich) was added via syringe. After stirring 2.5 h, the reaction was diluted with 150 mL EtOAc and washed 75 mL each, satd NH4C1, H2O, 10% NaHCO3 and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-{2-[methyl(methylsulfonyl)amino]phenyl}piperazine-carboxylate (700 mg). MS (ESI, pos. ion) m/z: 370 (M+H), (ESI, neg. ion) m/z: 368 (M−H). Calc'd for C17H27N3O4S: 369.48.
Reaction SMILES: [C:1]([N:8]([CH2:15][C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:21])=[CH:18][CH:17]=1)[CH2:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)(OC(C)(C)C)=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1C=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:28]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:34]=[CH:35][C:16]([CH2:15][N:8]([CH2:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH2:1][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)=[CH:17][CH:18]=1)[CH2:29][CH3:30]
Reactant: O=Cc1ccccn1
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)C(=O)OC(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ccccn2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 39.5 h

Procedure:
The compound (39.8 mg) obtained in Example 1-3 and pyridine-2-aldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (16.1 mg) were dissolved in anhydrous methanol (2.0 ml). The solution was added with sodium cyanoborohydride (18.9 mg) and then adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 39.5 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and then washed with a 1 mol/l sodium hydroxide and saturated saline solution, followed by drying with anhydrous magnesium sulfate. Subsequently, the residue was distilled off and the residue was then treated with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (7.00 mg) of the subject compound as a yellow solid.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:42][CH:41]=4)[C:38]([CH3:53])=[C:37]([OH:54])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:44][CH:45]=4)[C:38]([CH3:53])=[C:37]([O:54][CH3:3])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(OC2CCCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: CO
Product: COC1=C(C)C(c2ccc(OC3CCCCC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(4-(cyclohexyloxy)phenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.500 g, 1.24 mmol, 1 eq) and MeOH (10 ml); yield: 0.050 g (10%); MS m/z: 418.2 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 7.90 (s, 1H), 7.78 (s, 1H), 7.5 (s, 1H), 7.26 (s, 2H), 7.06 (d, 2H), 6.76 (d, 2H), 5.24 (s, 1H), 4.07 (d, 4H), 1.80 (d, 2H), 1.76 (d, 5H), 1.45 (d, 3H), 1.30 (d, 4H); HPLC (METHOD [A]): rt 15.23 min (100%)
Reaction SMILES: CSC.B(F)(F)F.C[N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32]C)=[C:25]([Cl:34])[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12].ClCCl>O>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:35])[C:18]=1[O:22][C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([OH:32])=[C:25]([Cl:34])[CH:24]=1)[C:14]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:36]
Reactant: COc1c(Cl)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: CC(C)c1cc(Oc2c(Cl)cc(C(=O)NCC(=O)O)cc2Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Boron trifluoride dimethyl sulfide (1.0 mL) was added at room temperature to a stirred solution of methyl-N-[3,5-dichloro-4-(3-chloro-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine (90 mg) and dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 24 hours, poured out in water and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (4×20 mL), concentrated and the resulting residue purified on column (silica gel, chloroform/methanol/acetic acid 94:6:0.65). This gave 53 mg (63%) of N-[3,5-dichloro-4-(3-chloro-4-hydroxy-5-isopropylphenoxy)benzoyl]glycine. LC-MS (ES+1): m/z 434.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29]([N:17]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4])[CH2:16][C:15]([O:14][CH3:13])=[O:18])=[O:30]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(CC(=O)c1ccc(Cl)cc1)C(=O)OC
Yield: 27.8 %

Procedure:
By substantially following the procedure given in Example 585c using 35 g (150 mmole) of 2-bromo-4'-chloroacetophenone, 20.7 g (160 mmole) of glycine methyl ester hydrochloride, 40.6 g (310 mmole) of diisopropylethyl amine, and 14.2 g (150 mmole) of methyl chloroformate, 12.5 g of the desired compound, an oil, was obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH:9]([OH:12])[C:8]3[CH:13]=[CH:14][O:15][C:7]=3[CH2:6]2)[CH2:3][CH2:2]1.[C:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])[NH2:17]>>[ClH:26].[C:16]([C:19]1[CH:24]=[CH:23][C:22]([O:12][CH:9]2[CH2:10][CH2:11][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:6][C:7]3[O:15][CH:14]=[CH:13][C:8]2=3)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])[NH2:17]
Reactant: OC1CCN(CC2CC2)Cc2occc21
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: Cl
Product: NC(=O)c1ccc(OC2CCN(CC3CC3)Cc3occc32)c(Cl)c1

Procedure:
The same method as in Example 3 was conducted using 7-cyclopropylmethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 39) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.C([Li])CCC.CCCCCC.CCOCC.I[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][Cl:40])=[CH:34][CH:33]=1>[Cl-].[Zn+2].[Cl-].O1CCCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][Cl:40])=[CH:34][CH:33]=3)[N:3]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1cccc(Br)n1
Reactant: ClCCc1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(-c2ccc(CCCl)cc2)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
To a 1 L 3-neck round-bottomed flask equipped with addition funnel and nitrogen inlet were added 10.0 g (40 mmol) 2-bromo-6-(2, 5-dimethylpyrrol-1-yl)pyridine and 200 mL dry tetrahydrofuran. The solution was cooled at −78° C., and a 1.6 M solution of butyl lithium in hexane (25 mL, 40 mmol) was added dropwise over 10 min. The reaction was stirred at −78° C. for 20 min, then a 1.0 M solution of zinc chloride in ether (100 mL, 100 mmol) was added dropwise over 40 min keeping the temperature at −70° C. The reaction was then allowed to warm to room temperature, and 11.0 g (40 mmol) 2-(4-iodophenyl)ethylchloride was added, followed by 200 mg tetrakistriphenylphosphine palladium. The reaction was refluxed for 3 hours, cooled, and filtered through Celite. The filtrate was evaporated, and the residue taken up in ethyl acetate, washed with brine, dried over sodium sulfate, and evaporated. The residue was filtered through silica gel with methylene chloride, concentrated, and chromatographed on silica gel using 1% ethyl acetate in hexane as eluant to afford 7.3 g (59%) of the product as an oil.
Reaction SMILES: [CH2:1]([N:3](CC)[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=O)[CH3:2].[C:34](=[O:37])([O-])[O-:35].[Na+].[Na+].OO.[OH2:42]>C(O)C>[CH2:1]([NH:3][CH2:4][CH3:6])[CH3:2].[C:30]([C:26]1[CH:25]=[C:24]([C:12]2([C:9]3[N:8]=[CH:7][C:6]([C:34]([OH:35])=[O:37])=[CH:11][N:10]=3)[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)[CH:29]=[CH:28][CH:27]=1)(=[O:42])[NH2:31]
Reactant: O
Reactant: O=C([O-])[O-]
Reactant: CCCC(C)CN1CCC(c2cccc(C#N)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CCCC(C)CN1CCC(c2cccc(C(N)=O)c2)(c2ncc(C(=O)O)cn2)CC1
Product: CCNCC
Reaction time: 24 h
Yield: 35 %

Procedure:
To a stirring solution of 2-[4-(3-cyano-phenyl)-1-(2-methyl-pentyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid diethylamide (90 mg, 0.20 mmol) in 1.5 mL ethanol (EtOH) at room temperature was added a 3 N solution of sodium carbonate (Na2CO3) (0.5 mL) and a 30% solution of hydrogen peroxide (H2O2) (0.14 mL). The reaction mixture was stirred for 24 hours, diluted with 10 mL water and extracted with EtOAc (3×15 mL). The combined organic layers were dried and concentrated. The crude material was purified by flash chromatography to afford 30 mg (35%) of the desired amide. 1HNMR (400 MHz, CDCl3) δ 8.71 (s, 2H), 7.89 (s, 1H), 7.58-7.51 (comp, 2H), 7.31 (t, 1H), 6.26 (br s, 1H), 5.88 (br s, 1H), 3.53-3.51 (comp, 2H), 3.26-3.25 (comp, 2H), 3.03-3.00 (comp, 2H), 2.75 (br s, 2H), 2.44-2.42 (comp, 2H), 2.15-2.02 (comp, 4H), 1.63-1.61 (comp, 1H), 1.36-1.16 (comp, 9H), 1.07-0.97 (comp, 1H), 0.87-0.83 (comp, 6H); MS (M+1) 466.3.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.[Cl:23][C:24]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([NH:30][C:2]2[N:3]=[CH:4][C:5]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[CH:27]=[CH:26][N:25]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Nc1ccnc(Cl)c1
Product: Cc1ccc2c(-c3cccnc3)cnc(Nc3ccnc(Cl)c3)c2n1

Procedure:
The title compound, MS: m/e=348.2/350.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-pyridineboronic acid and 2-chloro-4-aminopyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])=[CH:23][CH:24]=2)[CH:19]=[N:18]1)(=[O:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:14]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[N:12]=4)[C:28](=[O:29])[CH:27]=3)=[CH:23][CH:24]=2)[CH:19]=[N:18]1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Reactant: Nc1nc(-c2ccc(F)cc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(-c5ccc(F)cc5)nc4[nH]3)ccc21
Temperature: 170 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-1,2,4-triazol-5-amine (120 mg, 0.67 mmol) in diphenyl ether (2 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (650 mg, 2.36 mmol) and TsOH (5.76 mg, 0.03 mmol), and the resulting mixture was stirred for 5 h at 170° C. The reaction was then quenched by the addition of ethyl ether (8 ml). The solids were collected by filtration to afford 5-(1-acetyl-1H-indazol-5-yl)-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow crude solid (100 mg, crude).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)=O>>[CH3:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:3]([CH3:2])[C:4]=1/[CH:5]=[CH:30]\[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:34][CH2:33]1.[CH3:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:3]([CH3:2])[C:4]=1/[CH:5]=[CH:30]/[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1cccc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: Cc1cccc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Product: Cc1cccc(C)c1/C=C\C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
As starting materials, 5.00 g of (2,6-dimethylbenzyl)(triphenyl)phosphonium chloride and 1.79 g of tert-butyl 4-formylpiperidine-1-carboxylate were used and treated in the same manner as in Example 1. The reaction mixture was then purified by silica gel column chromatography (hexane-ethyl acetate) to give 192 mg of tert-butyl 4-[(Z)-2-(2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate (Example 2-1) and 1.96 g of tert-butyl 4-[(E)-2-(2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate (Example 2-2).
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[C:6]([I:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:12].C(N(S(F)(F)[F:19])CC)C>ClCCl>[F:19][C:7]1[C:6]([I:11])=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][C:3](=[O:12])[CH2:4]2
Reactant: O=C1Cc2c(I)cccc2N1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1Cc2c(ccc(F)c2I)N1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A suspension of 1,3-dihydro-1-hydroxy-4-iodo-2H-indol-2-one (2.43 g, 9 mmol) (prepared according to Kende et al., Synth. Commun. 20(14, 2133-2138 (1990)) in dry dichloromethane (500 mL) was cooled to −25° C. under an argon atmosphere with magnetic stirring. A solution of diethylaminosulfur trifluoride (DAST, 1.35 mL) (Aldrich) in dry dichloromethane (40 mL) was added dropwise at such a rate that the reaction temperature did not rise above −25° C. (about 15 min.) After stirring for an additional 30 min. at −25° C., the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (180 mL) and allowed to warm to room temperature. The mixture was then filtered through Celite® (Fisher) and the layers separated. The aqueous layer was extracted with dichloromethane (2×300 mL). The dichloromethane layers were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (magnesium sulfate) and concentrated. The resulting residue was purified by flash chromatography on silics gel using ethyl acetate—dichloromethane (1:7, V/V) as solvent to give 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (Yield 1.08 g, 43%).
Reaction SMILES: [C:1]([C@@:11]([C:28]([OH:30])=[O:29])([OH:27])[C@@:12]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:16])[C:13]([OH:15])=[O:14])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.O.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>CO>[C:17]([C@@:12]([C:13]([OH:15])=[O:14])([OH:16])[C@@:11]([C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([OH:27])[C:28]([OH:30])=[O:29])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Cl:32][C:33]1[CH:34]=[C:35]([C@:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: O
Product: OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine (S,S)-di-p-anisoyltartaric acid (14.77 g, 35 mmol), water (200 mL) and methanol (200 mL). Heat to reflux. Add dropwise, a solution of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (18.36 g, 70 mmol) in methanol (135 mL). After 1.5 hours, add water (135 mL) and slowly cool to ambient temperature to give a solid. Filter the solid that forms and rinse with water to give the title compound: mp; 201-202° C. (dec). Analysis by HPLC, as described in Example 5.1.1 indicates an enantiomeric excess of 99.9%, (99.9% ee). [α]2D0=+17.9° (c=1.00, dimethylsulfoxide).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:32]=[N:33][CH:34]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 186.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellow crystals. UPLC-MS (Condition 3) tR=1.08 min, m/z=479.4 [M+H]+, m/z=477.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.78-1.91 (m, 1H) 2.87 (d, J=11.29 Hz, 1H) 3.15-3.30 (m, 2H) 3.35-3.46 (m, 1H) 4.16-4.24 (m, 1H) 4.89 (d, J=3.39 Hz, 1H) 7.69 (d, J=8.66 Hz, 2H) 7.84 (dt, J=9.72, 2.16 Hz, 1H) 7.89-7.95 (m, 2H) 8.08 (d, J=2.38 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.64 Hz, 1H) 8.78 (d, J=2.26 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH:7]([NH:10][C:11](=[O:17])[C@@H:12]([NH2:16])[CH:13]([CH3:15])[CH3:14])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[C:4](=[O:22])[N:3]1[CH:23]([CH3:25])[CH3:24].[F:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35](O)=[O:36])[CH:30]=[C:31]([F:33])[CH:32]=1.CN(C)CCCN=C=NCC>ClCCl>[F:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35]([NH:16][C@@H:12]([CH:13]([CH3:15])[CH3:14])[C:11]([NH:10][CH:7]2[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[C:4](=[O:22])[N:3]([CH:23]([CH3:25])[CH3:24])[N:2]([CH3:1])[C:8]2=[O:9])=[O:17])=[O:36])[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)[C@H](N)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-amino-3-methyl-1-oxobutyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione (IIA, 1.44 mL, 0.28 mmol, 0.2 M solution in dichloromethane) in dichloromethane (2 mL) was added the solution of 3,5-difluorophenyl acetic acid (X, 2.16 mL, 0.43 mmol, 0.2 M solution in dichloromethane) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide polymer (0.72 g, 1.00 mmol) (Desai, et al., Tet. Lett, 1993, 34(48), 7685-7688). The resulting mixture was shaken on the shaker for 18 h and the resin was filtered off and washed with dichloromethane (2×1 mL). The combined solvent was collected and evaporated and product was analyzed by HPLC using the column YMC S7 C18 (3.0×50 mm) with a flow rate of 5.0 mL/min and gradient time of 2.0 min., starting with solvent A (10% MeOH—90% H2O—0.1% TFA), and ending with solvent B (90% MeOH—10% H2O—0.1% TFA). (70% yield).